Infection and chronic disease activate a brain-muscle signaling axis that regulates muscle performance

  1. Shuo Yang
  2. Meijie Tian
  3. Yulong Dai
  4. Shengyong Feng
  5. Yunyun Wang
  6. Deepak Chhangani
  7. Tiffany Ou
  8. Wenle Li
  9. Ze Yang
  10. Jennifer McAdow
  11. Diego E. Rincon-Limas
  12. Xin Yin
  13. Wanbo Tai
  14. Gong Cheng
  15. Aaron Johnson

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Abstract

Summary

Infections and neurodegenerative diseases induce neuroinflammation, but affected individuals often show a number of non-neural symptoms including muscle pain and muscle fatigue. The molecular pathways by which neuroinflammation causes pathologies outside the central nervous system (CNS) are poorly understood, so we developed three models to investigate the impact of neuroinflammation on muscle performance. We found that bacterial infection, COVID-like viral infection, and expression of a neurotoxic protein associated with Alzheimer′ s disease promoted the accumulation of reactive oxygen species (ROS) in the brain. Excessive ROS induces the expression of the cytokine Unpaired 3 (Upd3) in insects, or its orthologue IL-6 in mammals, and CNS-derived Upd3/IL-6 activates the JAK/Stat pathway in skeletal muscle. In response to JAK/Stat signaling, mitochondrial function is impaired and muscle performance is reduced. Our work uncovers a brain-muscle signaling axis in which infections and chronic diseases induce cytokine-dependent changes in muscle performance, suggesting IL-6 could be a therapeutic target to treat muscle weakness caused by neuroinflammation.

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  1. Version published to 10.1101/2020.12.20.423533v2 on bioRxiv
  2. ScreenIT

    SciScore for 10.1101/2020.12.20.423533: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableFlies were crossed at 25°C for two days; the progeny were raised at 29°C, and female adults were collected at day 3 post eclosure.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Immunohistochemistry and imaging: Antibodies used include anti-SARS-CoV-2-ORF3a (1:200, 101AP, FabGennix International Inc), anti-Tropomyosin (1:600, MAC141, Abcam).
    anti-SARS-CoV-2-ORF3a
    suggested: None
    anti-Tropomyosin
    suggested: (DSHB Cat# BB5/37.1, RRID:AB_2889799)
    Experimental Models: Cell Lines
    SentencesResources
    For LysoTracker staining, Hela cells were seeded in 6-well plates with cover slips and grown to 50% confluency at 37°C with 5%CO2 in Dulbecco’s modified Eagle’s medium (12430047, Invitrogen) supplemented with 10% heat-inactivated FBS (A4766801, Invitrogen).
    Hela
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    Drosophila genetics: The Gal4 stocks used to express SARS-CoV-2 ORF3a in brain, eye, and muscle included P(GAL4-elav.L) (Bloomington Stock Center, 8760), P(GAL4-ninaE.
    P(GAL4-elav.L)
    suggested: None
    GMR) (Bloomington Stock Center, 1104), and P(Mef2-GAL4.247) (Bloomington Stock Center, 50742).
    GMR)
    suggested: None
    P(Mef2-GAL4.247)
    suggested: None
    Transgenic Flies: UAS-SARS-CoV-2-ORF3a transgenic flies were generated by PCR-mediated subcloning of the SARS-CoV-2-ORF3a coding sequence (pDONR207 SARS-CoV-2 ORF3A, #141271, Addgene) into pUASt-Attb (EcoRI/XbaI).
    UAS-SARS-CoV-2-ORF3a
    suggested: None
    For Drosophila eye imaging, UAS-ORF3a/TM3, Sb flies were crossed with GMR-gal4 virgin flies to direct expression of ORF3a in eyes.
    UAS-ORF3a/TM3
    suggested: None
    For wild type control, w1118 flies were crossed with GMR-gal4 virgin flies.
    w1118
    suggested: None
    Software and Algorithms
    SentencesResources
    Projected in-focus images were produced with the Montage Multifocus module of the Zen Pro Software.
    Zen
    suggested: None
    Western blots were performed by standard method using precast gels (#456-1096, BioRad), and imaged with the ChemiDoc XRS+ system (BioRad).
    BioRad
    suggested: None
    Kaplan-Meier survival curves were generated, and statistical analysis was performed using log-rank analysis (Prism9, GraphPad Software).
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    All statistical analyses were performed with GraphPad Prism 9 software.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  3. Version published to 10.1101/2020.12.20.423533v1 on bioRxiv